DESCRIPTION: (Applicant's Description) Werner syndrome (WS) is an autosomal recessive human genetic disease that is associated with genetic instability and an elevated risk of cancer. The WS gene (WRN locus) encodes a 163 kDa protein that is a member of the RecQ helicase family. In the proposed research the applicants will test two hypotheses: 1) that the loss of WRN helicase activity causes genetic instability in WS; and 2) that WRN may limit genetic instability in vivo by insuring the accurate repair of DNA double-strand breaks (DSBs). Results of the proposed research will establish a causal link between the loss of WRN helicase function and genetic instability in WS cells. This project, in conjunction with other projects and Core A, aims to identify where the WRN protein functions in cellular nucleic acid metabolism, and how loss of function promotes genetic instability in human somatic cells. The investigators will also provide new information on DNA double-strand break repair in human somatic cells.